Abstract. Introduction

Enhanced In Vivo Activity of Cefditoren in PreImmunized Mice against Penicillin-Resistant S. pneumoniae (Serotypes 6B, 19F and 23F) in a Sepsis Model ...
Author: Jonas Gilbert
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Enhanced In Vivo Activity of Cefditoren in PreImmunized Mice against Penicillin-Resistant S. pneumoniae (Serotypes 6B, 19F and 23F) in a Sepsis Model Fabio Cafini1., Jose Yuste2., Maria-Jose Gime´nez1, David Sevillano1, Lorenzo Aguilar1*, Luis Alou1, Elisa Ramos-Sevillano2, Martha Torrico1, Natalia Gonza´lez1, Ernesto Garcı´a2, Pilar Coronel3, Jose Prieto1 1 Microbiology Department, School of Medicine, Universidad Complutense, Madrid, Spain, 2 Centro de Investigaciones Biolo´gicas (CSIC) and CIBER de Enfermedades Respiratorias (CIBERES), Madrid, Spain, 3 Scientific Department, Tedec-Meiji Farma S.A., Madrid, Spain

Abstract Background: Specific antibodies are likely to be present before S. pneumoniae infection. We explored cefditoren (CDN) total and free values of serum concentrations exceeding the MIC (t.MIC) related to efficacy in a mice sepsis model, and the effect of specific gammaglobulins on in-vitro phagocytosis and in-vivo efficacy. Methodology/Principal Findings: We used three pneumococcal isolates (serotype, MIC of CDN): Strain 1 (6B, 1 mg/ml), Strain 2 (19F, 2 mg/ml) and Strain 3 (23F, 4 mg/ml). Hyperimmune serum (HS) was obtained from mice immunized with heatinactivated strains. In-vitro, phagocytosis by HS diluted 1/10 in presence/absence of sub-inhibitory concentrations was measured by flow cytometry including fluorescent bacteria and a neutrophil cell line. In-vivo dose-ranging experiments with HS (dilutions 1/2–1/16) and CDN (6.25 mg/kg–100 mg/kg tid for 48 h) were performed to determine the minimal protective dilution/dose (highest survival) and the non-protective highest dilution/dose (highest mortality: HS-np dilution and CDN-np dose) over 7 days. Efficacy of CDN-np in animals pre-immunized with HS-np (combined strategy) was explored and blood bacterial clearance determined. The CDN measured protein binding was 86.9%. In-vitro, CDN significantly increased phagocytosis (vs. HS 1/10). In non pre-immunized animals, t.MIC values for CDN of